Cilia as cellular stress sensors
Prof. Dr. Gerd Walz (Renal Division, University Medical Center Freiburg)
Acute kidney injury commonly complicates severe illness in humans. Despite advances in supportive care, the fundamental programs that lead to repair and recovery of renal function remain poorly understood; attempts to facilitate the renal repair process have largely failed.
Using targeted laser-ablation in combination with time-lapse video microscopy, we found that directed cell migration is the prevailing repair mechanism in the developing zebrafish kidney. Surprisingly, early injuries (within the first 30 hours of embryogenesis) re not repaired; instead, the injured kidney tubule was irreversibly obliterated by a purse-string-like mechanism mediated by the formation of actomyosin bundles around the injured cells. Repair occurred independently of previously implicated factors such as fluid flow and cilia, and did not involve cellular de-differentiation or epithelial-mesenchymal transition. However, up-regulation of adhesion molecules seem critical to elicit a repair response and reconstitution of the kidney tubule. We propose to decipher the regulatory network that controls the repair process after tubular injury. Towards this goal, the pronephric duct of one- and two-day-old zebrafish embryos will be miro-dissected to determine differences in expression profiles. Transgenic fish with fluorescent pronephric ducts, FACS sorting and laser-capture techniques will be used to establish the temporal-spatial pattern of genes that control the migratory repair response. Newly identified transcription factors will be used in ChIP-on-chip to identify additional developmental targets. We will also analyze the actomyosin pathway in detail to determine which components of this pathway are drug-able and thus suitable for preclinical studies.